1. ¹Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
2. ²Program in Molecular Therapeutics, Duke University Medical Center, Durham, NC 27710, USA
3. ³North Carolina State University College of Veterinary Medicine, Raleigh, NC 27606, USA

Correspondence: Dwight D. Koeberl, DUMC Box 3528, Bell Building, Duke University Medical Center, Durham, NC 27710, USA. Fax: (919) 684 2362. E-mail: dwight.koeberl@duke.edu

^*Current address: Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA.

Received 1 October 2004; Revised 28 April 2005; Accepted 28 April 2005.

Abstract

Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid -glucosidase (GAA; acid maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Adeno-associated virus vectors containing either a liver-specific promoter (LSP) (AAV-LSPhGAApA) or a hybrid CB promoter (AAV-CBhGAApA) to drive human GAA expression were pseudotyped as AAV8 and administered to immunocompetent GAA-knockout mice. Secreted hGAA was detectable in plasma between 1 day and 12 weeks postadministration with AAV-LSPhGAApA and only from 1 to 8 days postadministration for AAV-CBGAApA. No anti-GAA antibodies were detected in response to AAV-LSPhGAApA (<1:200), whereas AAV-CBhGAApA provoked an escalating antibody response starting 2 weeks postadministration. The LSP drove approximately 60-fold higher GAA expression than the CB promoter in the liver by 12 weeks following vector administration. Furthermore, the detected cellular immunity was provoked by AAV-CBhGAApA, as detected by ELISpot and CD4⁺/CD8⁺ lymphocyte immunodetection. GAA activity was increased to higher than normal and glycogen content was reduced to essentially normal levels in the heart and skeletal muscle following administration of AAV-LSPhGAApA. Therefore, liver-restricted GAA expression with an AAV vector evaded immunity and enhanced efficacy in GSD-II mice.